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4.2 Posology and method of administration

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Posology

Adults with normal renal function (GFR ≥ 90 mL/min)

The recommended dose of Competact is 30 mg/day pioglitazone plus 1700 mg/day of metformin hydrochloride (this dose is achievable with one tablet of Competact 15 mg/850 mg, taken twice a day).

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Renal impairment

Competact should not be used in patients with renal failure or renal dysfunction (creatinine clearance< 60 ml/min) (see sections 4.3 and 4.4).

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3‑6 months.

The maximum daily dose of metformin should preferably be divided into 2‑3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin in patients with GFR < 60 mL/min.

If no adequate strength of Competact is available, individual monocomponents should be used instead of the fixed dose combination.

Hepatic impairment

Competact should not be used in patients with hepatic impairment (see sections 4.3 and 4.4).

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4.3 Contraindications

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Competact is contraindicated in patients with:

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

- Cardiac failure or history of cardiac failure (NYHA stages I to IV)

- Current bladder cancer or a history of bladder cancer

- Uninvestigated macroscopic haematuria

- Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock

- Hepatic impairment

- Acute alcohol intoxication, alcoholism

- Diabetic ketoacidosis or Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

- Ddiabetic pre-coma

- Severe rRenal failure or renal dysfunction (creatinine clearance GFR < 3060 mlL/min) (see section 4.4).

- Acute conditions with the potential to alter renal function such as:

- Intravascular administration of iodinated contrast agents (see section 4.4)

- Breast-feeding (see section 4.6)

4.4  Special warnings and precautions for use

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There is no clinical experience of pioglitazone in triple combination with other oral antidiabetic medicinal products.

Lactic acidosis

Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).

4.5       Interaction with other medicinal products and other forms of interaction

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There have been no formal interaction studies for Competact. The following statements reflect the information available on the individual active substances (pioglitazone and metformin).

Metformin

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Competact must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re‑evaluated and found to be stable, see sections 4.2 and 4.4.

Intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Competact (see section 4.4). Avoid consumption of alcohol and medicinal products containing alcohol.

Combinations requiring precautions for use

Some medicinal products that can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDS, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with Competact, close monitoring of renal function is necessary.

Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50% and C_max by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered

10. Date of revision of the text

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12^th Dec 2016

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4.4 Special warnings and precautions for use

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Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, p=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Available Eepidemiological data studies have also suggested a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, although not all studies identified a statistically significant increased risk in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short-term treatment cannot be excluded.

Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.

Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

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10. Date of revision of the text

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28^th April 2016

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4.3 Contraindications

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- Dehydration

- Severe infection

- Shock

- Intravascular administration of iodinated contrast agents (see section 4.4)

- Breast-feeding (see section 4.6)

4.4 Special warnings and precautions for use

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Others

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years. (see section 4.8)

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%). The observed excess risk of fractures for women on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use.

Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women. The risk of fractures should be considered in the long term care of patients treated with pioglitazone (see section 4.8).

Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered (see section 4.5).

4.8 Undesirable effects

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Summary of the safety profile

Clinical trials have been conducted with Competact tablets and co-administered pioglitazone and metformin (see section 5.1). Bioequivalence of Competact with co-administered pioglitazone and metformin has also been demonstrated (see section 5.2). At the initiation of the treatment abdominal pain, diarrhoea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously in most cases. Lactic acidosis is a serious reaction which may occur very rarely (< 1/10,000) (see section 4.4) and other reactions such as bone fracture, weight increase and oedema may occur commonly (≥ 1/100 to < 1/10) (see section 4.4).

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⁶ A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

In the 3.5 year PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. The observed excess risk of fractures for women on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%) (see section 4.4).

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4.9 Overdose

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No data are available with regard to overdose of Competact.

5.1 Pharmacodynamic Properties

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Competact combines two antihyperglycaemic active substances with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes mellitus: pioglitazone, a member of the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone and metformin combination

The fixed dose combination tablet of pioglitazone 15 mg/metformin 850 mg BID (N=201), pioglitazone 15 mg BID (N=189), and metformin 850 mg BID (N=210) were evaluated in type 2 diabetes mellitus patients with mean baseline HbA_1c of 9.5% in a randomised double-blind, parallel-group study. Previous anti-diabetic medicinal products medication was were discontinued for 12 weeks prior to baseline measurements. After 24 weeks of treatment, the primary endpoint of mean change from baseline in HbA_1c was -1.83% in the combination group versus -0.96% in the pioglitazone group (p< 0.0001) and -0.99% in the metformin group (p< 0.0001).

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The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes mellitus. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034

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5.3 Preclinical safety data

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Metformin

Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Environmental Risk Assessment (ERA)

No environmental impact is anticipated from the clinical use of pioglitazone.

6.1 List of excipients

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Film coat

Hypromellose

Macrogol 8000

Talc

Titanium dioxide (E171).

6.5 Nature and contents of container

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Aluminium/aluminium blisters.,

Ppacks of 14, 28, 30, 50, 56, 60, 90, 98, 112, 180.,

Multipack of 196 (2 packs of x 98) tablets and or 60 x 1 tablets in aluminium/aluminium perforated unit dose blisters in pack of 60 x 1 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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No special requirements. for disposal.

10. Date of revision of the text

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25^th April 2016

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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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‘‘For a full list of excipients’’

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‘’For the full list of excipients’’

4.2. Posology and method of administration

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The usual dose....

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The recommended dose.....

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4.3. Contraindications

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‘’Hypersensitivity to the active substance or to any of the excipients listed in section 6.1’’

4.4.  Special warnings and precautions for use

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“Bladder”

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“Bladder cancer”

4.6 Fertility, pregnancy and lactation

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4.8. Undesirable effects

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“in less than 1 case per 10,000 patients”

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“very rarely (< 1/10,000)”

“in less than 1 case per 10 patients”

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“commonly (≥ 1/100 to < 1/10)”

“Within each frequency grouping, adverse reactions are presented in order of decreasing incidence and seriousness”

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“Within each system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness.”

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5.1. Pharmacodynamic properties

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5.2     Pharmacokinetic properties

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5.3 Preclinical safety data

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“Environmental Risk Assessment: no environmental impact is anticipated from the clinical use of pioglitazone.”

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“Environmental Risk Assessment (ERA)

No environmental impact is anticipated from the clinical use of pioglitazone.”

7.

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“Takeda Pharma A/S

Langebjerg 1

DK-4000 Roskilde

Denmark”

to

“Takeda Pharma A/S

Dybendal Alle 10

2630 Taastrup

Denmark”

10. DATE OF REVISION OF THE TEXT

Changed to:

23/07/2014

Updated SmPC wording (main changes to be aware of)

Summary of change

4.4 Special Warnings and Precautions for use

Monitoring of liver function

Addition of elevated liver enzymes and that there have been some fatal reports.

4.7       Effects on ability to drive and use machines

Competact has no or negligible effect on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.

Following wording has been added, previous wording was ’ No effects on ability to drive and use machines have been observed.’

4.8     Undesirable effects

          At the initiation of the treatment abdominal pain, diarrhoea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously in most cases. Lactic acidosis is a serious reaction which may occur in less than 1 case per 10,000 patients (see section 4.4) and other reactions such as bone fracture, weight increase and oedema may occur in less than 1 case per 10 patients (see section 4.4).

No new events have been reported, but the information is now presented in a table and the following wording added to introduction of section

5.1 Pharmacodynamic properties

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Competact in all subsets of the paediatric population in Type 2 Diabetes Mellitus. See section 4.2 for information on paediatric use.

Following wording has been added

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Added at the end of the SmPC